Single gene evolution helped Black Death kill millions for centuries

By Stephen Beech

The evolution of a single gene allowed the Black Death to adapt, survive and kill tens of millions of people, reveals new research.

Scientists have uncovered the way a gene in the bacterium that causes bubonic plague, Yersinia pestis, allowed it to survive hundreds of years by adjusting its virulence and the length of time it took to kill its victims, before eventually dying out.

The study, published in the journal Science, addresses key questions about how pandemics enter human populations, cause immense sickness, and evolve different levels of virulence.

The Black Death remains the single deadliest pandemic in recorded human history, wiping out up to half of the populations of Europe, Western Asia and Africa.

It first appeared in the 14th Century before re-emerging in waves over more than 500 years, persisting until 1840.

The Black Death was caused by the same bacteria that caused the Plague of Justinian, the first plague pandemic that had broken out in the 6th Century.

The third plague pandemic began in China in 1855 and continues today.

Its deadly effects are now more controlled by antibiotics, but are still felt in regions like Madagascar and the Democratic Republic of Congo, where cases are regularly reported.

The new study was conducted by researchers at McMaster University in Canada and France’s Institut Pasteur.

Co-senior author Professor Hendrik Poinar, director of the McMaster Ancient DNA Centre, said: "This is one of the first research studies to directly examine changes in an ancient pathogen, one we still see today, in an attempt to understand what drives the virulence, persistence and/or eventual extinction of pandemics.”

He said strains of the Justinian plague became extinct after 300 years of ravaging European and Middle Eastern populations.

Strains of the second pandemic emerged from infected rodent populations, causing the Black Death, before breaking into two major lineages.

Poinar explained that one of those two lineages is the ancestor of all present-day strains. The other re-emerged over centuries in Europe and ultimately went extinct by the early 19th Century.

Using hundreds of samples from ancient and modern plague victims, the team screened for a gene known as pla, a high-copy component of Y. pestis, which helps it move through the immune system undetected to the lymph nodes before spreading to the rest of the body.

Genetic analysis revealed that its copy number, or total number of pla genes found in the bacterium, had decreased in later outbreaks of the disease, which in turn decreased its mortality by 20% and increased the length of its infection, meaning the hosts lived longer before they died.

The studies were performed in mouse models of bubonic plague.

When the pla gene was in its original, high copy number, the disease was much more virulent and killed each of its hosts, and did so much quicker.

The research team also identified a "striking" similarity between the trajectories of modern and ancient strains, which independently evolved similar reductions in pla in the later stages of the first and second pandemic, and so far, in three samples from the third pandemic, found in Vietnam today.

In both the Justinian and Black Death plagues, the evolutionary change occurred around 100 years after the first outbreaks.

The researchers propose that when the gene copy number dropped and the infected rats lived longer, they could spread infection farther, ensuring the reproductive success of the pathogen.

Poinar said: “The reduction of pla may reflect the changing size and density of rodent and human populations.

“It’s important to remember that plague was an epidemic of rats, which were the drivers of epidemics and pandemics. Humans were accidental victims.”

He says black rats in cities likely acted as “amplification hosts” due to their high numbers and proximity to humans.

Because black rats are highly susceptible to Y. pestis, the pathogen needed rat populations to stay high enough to supply new hosts for Y. pestis to persist and allow the pandemic cycle to continue.

However, the pla-reduced strains eventually went extinct, likely reflecting another shift in the host-pathogen relationship within their environment.

When the research team searched for signs of depletion in a large set of samples of the third pandemic preserved in a collection at the Institut Pasteur, they found three contemporary strains with pla depletion.

Co-senior author Dr. Javier Pizarro-Cerdá, of Institut Pasteur, said: “Thanks to our international collaborators who monitor local epidemics of plague worldwide, we were able to find the unique bacterial samples used for this project, akin to finding of three rare needles in a haystack."

Co-lead author Dr. Guillem Mas Fiol, also of Institut Pasteur, said: “One of the most interesting aspects of our research was the possibility to explore a feature first observed in extinct plague strains, that could, for the first time, be experimentally tested in living contemporary bacterial strains.”

Co-lead author Ravneet Sidhu, a PhD candidate at the McMaster Ancient DNA Centre, added: “Although our research sheds light on an interesting pattern in the evolutionary history of plague, the majority of strains which continue to circulate today in Africa, South America and India are the more virulent ones, the ones that were previously responsible for massive mortality.”